Development of novel diagnostic approaches based on pulmonary physiology: applications in acute pulmonary embolism and obstructive sleep apnea

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(1)Development of novel c approachesapproaches based on Development ofdiagnos� novel diagnos�c pulmonary physiology based on pulmonary physiology Applica�ons in acute pulmonary embolism and Applica�ons in acute pulmonary obstruc� ve sleep apnea embolism and obstruc�ve sleep apnea. T.M. Fabius. T.M. Fabius.

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(3) Development of novel diagnostic approaches based on pulmonary physiology Applications in acute pulmonary embolism and obstructive sleep apnea. T.M. Fabius.

(4) This dissertation has been approved by: Supervisor:. Prof. Dr. J.A.M. van der Palen. Co-supervisors:. Dr. Ir. F.H.C. de Jongh. . Dr. M.G.J. Brusse-Keizer. Development of novel diagnostic approaches based on pulmonary physiology: Applications in acute pulmonary embolism and obstructive sleep apnea Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede, the Netherlands; Department of Research Methodology, Measurement, and Data-analysis, Faculty of Behavioral Sciences, University of Twente, Enschede, the Netherlands. Thesis, University of Twente, 2019. ISBN: . 978-90-365-4763-5. DOI: . 10.3990/1.9789036547635. Printed by:. Gildeprint, Enschede. © Copyright 2019: Timon Fabius, Hengelo, the Netherlands. All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, without prior permission of the author..

(5) Development of novel diagnostic approaches based on pulmonary physiology Applications in acute pulmonary embolism and obstructive sleep apnea. DISSERTATION to obtain the degree of doctor at the University of Twente, on the authority of the rector magnificus, prof.dr. T.T.M. Palstra, on account of the decision of the doctorate board, to be publicly defended on Friday the 21st of June 2019 at 14.45 hours by Timon Matthijs Fabius born on the 16th of August 1991 in Leiden, the Netherlands.

(6) Graduation Committee Chairman Prof. Dr. T.A.J. Toonen . University of Twente. Supervisor Prof. Dr. J.A.M. van der Palen . University of Twente. Co-supervisors Dr. Ir. F.H.C. de Jongh . University of Twente. Dr. M.G.J. Brusse-Keizer . Medisch Spectrum Twente. Members Prof. Dr. Ir. P.H. Veltink . University of Twente. Prof. Dr. J.G. Grandjean . University of Twente. Prof. Dr. N. de Vries . Academisch Centrum Tandheelkunde Amsterdam. Prof. Dr. H.J. Bogaard . Amsterdam UMC. Dr. J.G. van den Aardweg . Amsterdam UMC.

(7) Contents Chapter 1. General Introduction. 7. Chapter 2. The TL,NO / TL,CO ratio cannot be used to exclude pulmonary embolism. 21. Chapter 3. Volumetric capnography in the exclusion of pulmonary embolism at the. 33. emergency department: a pilot study Chapter 4. Retrospective validation of a new volumetric capnography parameter. 47. for the exclusion of pulmonary embolism at the emergency department Chapter 5. Validation of the oxygen desaturation index in the diagnostic workup of. 61. obstructive sleep apnea Chapter 6. The use of oximetry and a questionnaire in primary care enables. 75. exclusion of a subsequent obstructive sleep apnea diagnosis Chapter 7. Exhaled breath analysis in the diagnosis of obstructive sleep apnea. 91. Chapter 8. General Discussion. 103. Summary. 119. Samenvatting. 127. Dankwoord. 135. Curriculum vitae. 143.

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(9) General Introduction. T.M. Fabius.

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(11) 1. The aim of the research presented in this thesis was to develop and validate diagnostic approaches for acute pulmonary embolism and obstructive sleep apnea. Though these pathologies have many disparate characteristics, they share one important feature. Both pulmonary embolism and obstructive sleep apnea impair the main function of the lungs: gas exchange (i.e. the uptake of oxygen and the removal of carbon dioxide). This shared feature was used for the development of novel diagnostic tools. In this chapter, an introduction to acute pulmonary embolism and obstructive sleep apnea is presented.. Acute Pulmonary Embolism Acute pulmonary embolism (PE) is an acute obstruction of blood flow through the pulmonary arteries. Often, this obstruction is caused by a blood clot that originated from the deep peripheral veins in the legs. PE is common and requires treatment when diagnosed. In 2016 in the Netherlands, PE accounted for more than 16.000 hospital admissions and was listed as primary cause of death in 340 cases [1,2]. Though subjects suffering from PE may have severe complaints (e.g. dyspnea, thoracic pain, tachycardia, hemoptysis) it may also present without apparent symptoms [3]. The cornerstone of the treatment of PE is anticoagulation [4]. Management of the acute phase of PE depends on its severity. In hemodynamically unstable patients reperfusion using thrombolysis is warranted [5]. Of the stable patients, some become unstable within 24 to 48 hours after diagnosis. To identify these patients, risk stratification should be applied. The Pulmonary Embolism Severity Index (PESI) uses eleven several clinical characteristics to classify patients into five categories (from very low to very high risk of adverse events) [6]. Due to the complexity of the original version of the PESI, a simplified version was developed (sPESI) [7]. The sPESI is considered aberrant if the patient is either aged > 80 years, has a history of cancer, has a history of heart failure or chronic lung disease, has a pulse rate ≥ 110/min, has a systolic blood pressure < 100 mmHg or has an arterial oxyhemoglobin saturation <90% [7]. If none of these criteria are present (i.e. the sPESI score is normal) there is a low risk of adverse events within 30 days after diagnosis and home treatment may be considered [8]. If the risk of adverse events is determined to be intermediate (i.e. the patient is hemodynamically stable but the sPESI or some other stratification rule is aberrant) the patient should be admitted and estimates of right ventricle overload and cardiac markers should be obtained. This can be done using imaging findings (such as the ratio of the width of the right ventricle to the width of the left ventricle [9]) and determination of laboratory markers of right ventricular dysfunction (such as N-terminal-pro brain natriuretic peptide (NT-proBNP) [10]) or myocardial injury (such as troponin [11]). If aberrant markers are found, close monitoring of vital functions should be applied during the first 48 – 72 hours to enable early recognition of deterioration [8].. General Introduction. 9.

(12) Depending on the extent of the obstruction, PE may result in significant increased load on the right ventricle and hypoperfusion of the parts of the lung distal to the obstruction. As ventilation of these parts is unaltered, a ventilation / perfusion mismatch will occur (i.e. dead space ventilation). This may result in hypoxemia. An increase in arterial carbon dioxide levels may also be present but is likely to be corrected due to a compensatory increase in ventilation. The physiologic effects of PE (increased vascular resistance and dead space ventilation) are potentially lethal. The mortality of untreated PE is often reported as 20 – 30% based on a small randomized controlled trial in the early 1960s [12]. If treated properly, mortality decreases substantially [13]. However, even with treatment, mortality within three months after diagnosis may still be substantial, but probably influenced by comorbidities associated with PE [14]. Given the high mortality rate and potential beneficial effects of treatment, a definite exclusion of PE is warranted when it is suspected. However, diagnosis of PE can be challenging as symptoms (mostly dyspnea and thoracic pain) are nonspecific. Several strategies have been developed to determine the risk of PE. These strategies often use a clinical decision rule (such as the Wells or revised Geneva score [15,16]) in combination with the D-dimer level in the blood. A low or moderate clinical probability combined with a D-dimer below 500 µg/L safely excludes PE [17]. If the clinical probability is high or the D-dimer is above 500 µg/L, imaging is warranted. The gold standard imaging technique for the confirmation or exclusion of PE is a ventilation / perfusion scan or computed tomography pulmonary angiography (CTPA) [8]. Despite the use of the previously mentioned selection strategies, PE is still confirmed in only 20-30% of the CTPA scans [18]. Due to the inherent limitations of these imaging techniques (i.e. costs, limited availability and requirement of irradiation) several improvements to increase the specificity of the previously mentioned screening strategies have been proposed. It was recognized that D-dimer levels increase with age. This lead to the development of an age-dependent cutoff for the D-dimer level (i.e. 10 times the age with a minimum of 500 µg/L) [19]. A large randomized trial showed no differences in thromboembolic events after three months between the group with a static cutoff and the age-adjusted cutoff [20]. Another study identified the three most important items of the Wells-score (i.e. clinical signs of deep venous thrombosis, hemoptysis and PE being the most likely diagnosis) and implemented them in the YEARS algorithm [21]. If either one of the mentioned items is present, the conventional D-dimer cutoff of 500 µg/L should be applied. If none of the items is present, a D-dimer cutoff of 1000 µg/L can be used. In a large validation study, applying the YEARS algorithm did not lead to more thromboembolic events and need for CTPA scans was decreased with 14% compared to the conventional strategy of a static cutoff combined with the Wells-score [22]. In the first chapters of this thesis we investigated if measurements which may indicate impaired gas exchange, can safely be applied to exclude PE. If so, they might be used to decrease the need for imaging and thus potentially decrease costs and diagnostic delay. In chapter 2, we first tested the diagnostic accuracy of the diffusion capacity of the lungs for carbon monoxide and nitric oxide. As PE obstruct a part of the pulmonary vasculature, it seems logical that the 10. Chapter 1.

(13) 1. diffusion capacity is decreased. Indeed, several studies have shown that the diffusion capacity (or transfer factor) for carbon monoxide is decreased in PE [23,24]. For nitric oxide however, this decrease in diffusion capacity may be absent as the binding capacity for nitric oxide with hemoglobin is much higher compared to carbon monoxide making it virtually non-dependent to the vascular component of diffusion capacity [25]. The ratio of the diffusing capacity of the lungs for carbon monoxide and nitric oxide might thus indicate pulmonary vascular abnormalities [26]. One study in sheep showed that acute obstruction of a pulmonary artery indeed increases this ratio [27]. However, whether the nitric oxide / carbon monoxide transfer factor ratio is also affected in humans with PE has not been investigated earlier. In chapter 2 we measured the diffusion capacity in patients presenting to the emergency department due to suspected PE. The results of the diffusion measurements were compared with the results of the CTPA scan to determine the diagnostic accuracy of the nitric oxide / carbon monoxide transfer factor ratio for the exclusion of PE. In chapter 3 we investigated the use of another physiologic measurement, volumetric capnography, for the exclusion of PE. Volumetric capnography can be used to reflect dead space ventilation [28]. Most studies using capnography in the diagnostic process of PE either used only end-tidal carbon dioxide levels or the combination of end-tidal carbon dioxide with arterial carbon dioxide levels [29]. In chapter 3 we obtained volumetric capnograms in subjects presenting to the emergency department with suspected PE. We specifically compared a novel parameter, which combines conventional capnography parameters (without the need for arterial blood gas analysis) with the results of the CTPA scans, and sought to determine a cutoff that could safely exclude PE (i.e. a negative predictive value of 100%). In chapter 4 we used the data of a previous large study on volumetric capnography in the diagnostic process of PE to perform an external validation of the novel capnography parameter and the cutoff identified in chapter 3. Obstructive Sleep Apnea The hallmark feature of obstructive sleep apnea (OSA) is repetitive breathing stops during sleep caused by an obstruction of the upper airway. The frequent breathing stops cause sleep fragmentation. Consequently, patients suffering from OSA often experience snoring, excessive daytime sleepiness, morning headaches, and mood swings [30]. Paradoxically, patients also often complain about insomnia [31]. Apart from the clinical symptoms, patients have an increased risk of traffic accidents [32] and an increased risk of many comorbidities such as myocardial infarction and stroke [33,34]. Though obesity is often indicated as the main cause of OSA, its exact pathogenesis is more complex and still not fully understood. Research over the past two decades has shown that mechanical collapsibility is an important aspect but other factors such as sensitivity and responsiveness to decreasing intrathoracic pressures (caused by an apnea) may also be vital for the development of OSA [35,36]. The severity of OSA is often expressed as the amount of apneas and hypopneas per hour sleep, represented in the apnea-hypopnea index (AHI). The prevalence of OSA highly depends General Introduction. 11.

(14) on the definition that is used. A study in the early 1990s estimated that approximately two to four percent of middle-aged men has an AHI ≥ 5 and associated symptoms [37]. Despite this high prevalence, it was estimated that approximately 93% of all women and 82% of all men with moderate or severe OSA (i.e. AHI ≥ 15) were not clinically diagnosed [38]. Regardless of the definition used, the prevalence of OSA increased substantially over the past decades. In 2013, a relative increase of 14% and 55% (depending on the subgroup) was reported [39]. In 2015, a large population based study from Switzerland reported an even higher prevalence for moderate-to-severe sleep apnea (defined as an AHI ≥ 15); 23.4% in middle-aged women and 49.7% in middle-aged men [40]. It should be noted that this study did not require the presence of associated symptoms for an OSA diagnosis. The gold standard for the diagnosis of OSA is full in-laboratory polysomnography (PSG) [41]. Full PSG may include the nightly measurement of: oximetry, airflow, snoring, respiratory effort, end-tidal carbon dioxide, esophageal pressure, electrocardiography (ECG), electroencephalography (EEG), actigraphy, electromyography (EMG), electrooculography (EOG) and video recordings. Using all these signals, sleep wake activity, respiration and muscle activity can be scored reliably during sleep. According to the most recent American Academy of Sleep Medicine (AASM) guidelines, an apnea is defined as a decrease in airflow of at least 90% regardless of other physiologic signals [42]. A hypopnea is defined as a decrease in airflow of 30-90% accompanied by a significant desaturation (≥ 3 or 4%) or an arousal [42]. Performing a full PSG is expensive both in terms of time and costs. Given the high prevalence of OSA, portable monitoring (PM) was developed to reduce the need for in-laboratory PSG. PM is performed in the patient’s home and typically consists of less signals than full PSG. When there is no objective measurement of sleep (i.e. no EEG, EMG and EOG) a PM is often referred to as polygraphy (PG). The obvious downside of PG vs PSG is that sleep is not measured accurately and thus the denominator of the AHI may not be correct. Moreover, arousals cannot be determined and thus will hypopneas with arousal but without significant desaturations be missed. Consequently, a PG is likely to result in a lower AHI compared to a PSG. However, if clinical suspicion of OSA is high and there are no relevant comorbidities, PG is considered sufficient for confirmation of the diagnosis [41,43]. For exclusion of OSA however, PSG is still considered the only right tool. According to the results of a large questionnaire of the Dutch Apnea Society, most patients evaluated for OSA in the Netherlands underwent PG [44]. Despite the lower costs of PG compared to PSG, they are still substantial. This prohibits the use of PG for screening of large populations. To be able to select those who are at increased risk (and should therefore get further testing) many questionnaires have been developed. An example of an often used questionnaire is the STOP-BANG questionnaire, which consists of eight items (Snoring, Tiredness, Observed apneas, hyPertension, BMI, Age, Neck-circumference and Gender), and results in a score between 0 to 8 [45]. This questionnaire was originally developed for the pre-operative setting to select patients who are at increased risk of OSA and therefore for peri- and post-operative complications [45]. A score on the STOP-BANG ≥ 5 has a sensitivity of 36% and specificity of 80% for an AHI>5 [46]. 12. Chapter 1.

(15) 1. A recent study in the Netherlands developed a two-step screening strategy using a questionnaire (the Philips Questionnaire) and nasal flow recording. If the questionnaire indicates a low risk of OSA, no further investigation is needed. If the questionnaire shows a high risk of OSA, referral to a sleep center should be made. If the questionnaire shows an intermediate risk of OSA, nasal flow recording should be performed to decide whether sleep center evaluation is indicated. In a company workers population this strategy resulted in a sensitivity of 63% with a specificity of 90% [47]. Long-term management of OSA should always include lifestyle modification when indicated (e.g. weight loss and abstention of alcohol). The remaining treatment options for OSA depends on its severity. According to the AASM, an AHI 5-15 is considered as mild, an AHI 15-30 as moderate and an AHI ≥ 30 as severe OSA [48]. In moderate-to-severe cases (i.e. AHI ≥ 15), treatment with continuous positive airway pressure (CPAP) is usually indicated. The positive pressure that is applied through a (oro-)nasal mask prohibits collapse of the upper airway. As it only prevents the airway from collapsing and does not treat the cause of OSA, CPAP should be used continuously during sleep. Generally, CPAP normalizes the AHI but compliance to the treatment is often poor with non-adherence rates reported up to 40% [49,50]. In cases with mild or moderate OSA (i.e. AHI 5-30), a mandibular advancement device (MAD) might be beneficial. The protrusion of the lower mandible enlarges the upper airway surface and thereby reduces the chance on collapse. The effect of MAD therapy on the AHI is lower compared to CPAP (mean difference in decrease of AHI approximately 8 events/hour), but overall compliance is substantially higher (approximately one hour/night) and the effect on symptoms is similar [51,52]. Surgery (such as uvulopalatopharyngoplasty or bimaxillary osteotomy) may be useful in subjects with evident anatomical impairments such as enlarged tonsils or a severe retrognathia. Again, the effect on the AHI is generally lower than CPAP with only approximately 30% of the cases reaching an AHI<10, but all subjects are completely compliant (for obvious reasons) [53]. In patients with positional OSA (i.e. only an increased AHI in supine position), positional therapy (i.e. avoiding a supine sleeping position) may be an effective tool. If the nonsupine AHI is normal (< 5), positional therapy is as effective as CPAP and MAD therapy in normalization of the AHI [54,55]. To prevent the supine position, putting a tennis ball or other bulky mass between the shoulder blades is as effective as more advanced devices such as the Sleep Position Trainer, which measures position and starts vibrating in supine position. However, in a randomized controlled trial, compliance and sleep quality were significantly in favor of the Sleep Position Trainer [56]. One of the most recent treatment options for OSA is hypoglossal nerve stimulation. By stimulating the hypoglossal nerve during sleep, the genioglossus muscle is activated and thereby collapse of the upper airway may be prevented. In a large trial in strictly selected OSA patients (AHI ≥ 15, BMI < 32 and no relevant neuromuscular, cardiovascular or psychiatric comorbidities) with CPAP failure, hypoglossal nerve stimulation successfully reduced the AHI and improved symptoms and self-reported compliance was high (86%) [57].. General Introduction. 13.

(16) As outlined above the prevalence of OSA is high and increasing but its diagnosis requires laborious testing. This has caused many sleep centers to reach the maximum of their capacities. Therefore, there is a high need for simple, cheap and easily applicable measurement methods for the screening of OSA, which might decrease the need of “unnecessary” referrals (i.e. subjects who do not have OSA). Oximetry seems to satisfy the requirement of being cheap, simple and easily applicable. To determine its validity for the screening of OSA we first investigated the resemblance of the oxygen desaturation index (ODI, which can be determined using oximetry only) and the AHI in a large sleep center PG database in chapter 5. We specifically aimed to determine a cutoff for the ODI that excludes an aberrant AHI (i.e. ≥ 5). In chapter 6 we prospectively investigated the diagnostic accuracy of this cutoff and its combination with the Philips questionnaire to exclude a sleep center OSA diagnosis in patients with suspected OSA in primary care. In chapter 7 we investigated the use of another potential screening tool; exhaled breath measurements. We hypothesized that the many systemic processes caused by OSA may be reflected in exhaled breath. In chapter 7 we primarily aimed to identify the diagnostic accuracy of exhaled breath measurements to discriminate patients who have a clinical suspicion of OSA but an AHI<15 from patients with an AHI≥15. Secondly, we aimed to identify which OSA related parameter seems to have the most influence (specifically AHI or hypoxemia related parameters) on exhaled breath profiles.. Outline of this thesis In chapter 2 we investigated the transfer factor of the lungs for carbon monoxide and nitric oxide for the exclusion of PE. In chapter 3, we developed a novel parameter based on conventional volumetric capnography parameters for the exclusion of PE. This novel parameter was externally validated in chapter 4. In chapter 5 we compared oximetry (expressed as the oxygen desaturation index (ODI)) to the AHI. The findings of this study were used to develop a two-step strategy using the ODI and the Philips questionnaire to screen for OSA in primary care. This strategy was prospectively validated in chapter 6. In chapter 7 we investigated if exhaled breath profiles can be used to distinguish OSA from non-OSA subjects. Finally, chapter 8 discusses the findings of the presented research in a broader context.. 14. Chapter 1.

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(23) The TL,NO / TL,CO ratio cannot be used to exclude pulmonary embolism. T.M. Fabius M.M. Eijsvogel I. van der Lee M. Brusse-Keizer F.H. de Jongh. Clin Physiol Funct Imaging 2017;37:400–4. doi:10.1111/cpf.12317..

(24) Abstract Background The existing screening modalities for pulmonary embolism (PE), such as D-dimer and clinical prediction rules, have low positive predictive values. With its capability to indicate pulmonary vascular abnormalities, the ratio of the transfer factor of the lungs for nitric oxide and the transfer factor of the lungs for carbon monoxide (TL,NO/TL,CO) might be an additional discriminating parameter.. Methods CO/NO diffusion measurements were performed on unselected patients seen on the emergency department for which due to suspected PE a computed tomography pulmonary angiogram (CTPA) was ordered.. Results A total of 28 patients were included, PE was found in 12 on CTPA. Median TL,NO/TL,CO ratio was 4.09 (IQR 3.83 – 4.40) in the no PE group versus 4.00 (IQR 3.78 – 4.32) in the PE group(p=0.959). Median alveolar volume was 77.1% of predicted in the no PE group versus 71.0% of predicted in the PE group (p=0.353). Median TL,CO was 75.8% of predicted in the no PE group versus 68.8% of predicted in the PE group (p=0.120). Median TL,NO was 69.3% of predicted in the no PE group versus 60,5% of predicted in the PE group (p=0.078).. Conclusion The presented data indicate that the TL,NO/TL,CO ratio cannot be used to exclude PE.. 22. Chapter 2.

(25) 1. Introduction 1. Introduction. 2. Due toDue itstopotentially consequences, pulmonary embolism be ruled out its potentiallylethal lethal consequences, pulmonary embolism (PE) needs(PE) to be needs ruled outtowhen when suspected. suspected. nowadays used tools to select patientsof with TheThe nowadays widely widely used tools to select patients with suspicion PE aresuspicion D-dimer [1] of PE are D-dimer and Wells-score Positive D-dimer or high Wells-score warrant Current further investigaand[1] Wells-score [2]. Positive[2]. D-dimer or high Wells-score warrant further investigation. golden standard confirm orto exclude PE is or a computed pulmonarytomography angiogram (CTPA) tion. Current goldentostandard confirm excludetomography PE is a computed pulmonary [3]. In (CTPA) over 75%[3]. of all dueCTPAs to suspected PE, thedue disease can be safely PE, ruledthe outdisease [4]. angiogram InCTPAs overrequested 75% of all requested to suspected can To prevent unnecessary and admissions due to the need foradmissions prehydration,due an additional be safely ruled out [4]. To irradiation prevent unnecessary irradiation and to the need for fast and cheap tool to exclude is desirable. Withto its exclude capability PE to indicate pulmonary vascular prehydration, an additional fastPEand cheap tool is desirable. With its capability to abnormalities, TL,NO/TL,COabnormalities, ratio might be such a tool. indicate pulmonarythevascular the TL,NO/TL,CO ratio might be such a tool.. ) for can be described by the equation: Roughton-Forster The factorof of Thetransfer transfer factor the the lungslungs (TL) for(T a Lgas canabegas described by the Roughton-Forster. equation:. 1 1 1 = + 𝑇𝑇𝐿𝐿 𝐷𝐷𝐷𝐷 𝜃𝜃𝑉𝑉𝑐𝑐. in which Dm indicates the membrane diffusion capacity, θ the binding capacity of the gas with the. in which Dm indicates the membrane diffusion capacity, θ the binding capacity(CO) of the gas erythrocytes and VC the pulmonary capillary blood volume [5]. In the case of carbon monoxide. blood [5]. In theθVcase of carbon with the C the pulmonary the erythrocytes transfer factor isand moreVweighted by θVC thancapillary on Dm. In the casevolume of nitric oxide (NO), C is much on Dm.onInDm the case monoxide (CO) factor morefactor weighted C than greater thanthe Dm transfer [6]. Therefore, the is transfer of NO (Tby is more dependent than on of nitric L,NO)θV much greater than Dmthat, [6].given Therefore, the transfer of αNO oxide (NO), θVC isand θVC. Hughes van der Lee have shown that DmNO equals αDmCOfactor (in which is a(TL,NO) is more Hughes vanfactor der for LeeCOhave that,ongiven that dependent onconstant), Dm than θVofC.TL,NO theoretic theon ratio and theand transfer (TL,CO)shown is dependent the Dm/V C Dm NO and As which α is (assumed a constant, the TL,NO/ Tthe is aof reflection of thethe Dm/V (in α is to a be) theoretic constant), ratio TL,NO and transfer factor equalsratio αDm L,CO ratio C ratio COα. need of further of this might thus suggest pulmonary is dependent onassumptions. the Dm/VAC rise ratio andratio α. As α is (assumed to be) avascular constant, the for COwithout (TL,CO) the [7]The TL,NO/ TL,CO beenC reported to be increased in heavy smokers assumptions. [8], ofratio thehas Dm/V ratio without the need of further A TL,NO/ Tabnormalities. L,CO ratio is a reflection thromboembolic diffuse parenchymal lung disease In the / TL,CO ratio rise ofchronic this ratio might thuspulmonary suggesthypertension pulmonaryand vascular abnormalities. [7]The[9].TL,NO casereported of PE, one would VC to beindecreased and therefore L,NO/ TL,CO to be increased. This has has been to beexpect increased heavy smokers [8], Tchronic thromboembolic pulmonary. been investigated in prone anesthetized sheep by Harris et al. who reported a significant higher TL,NO/ hypertension and diffuse parenchymal lung disease [9]. In the case of PE, one would expect T. ratio after pulmonary artery obstruction compared to baseline [10]. To the best of our. L,CO decreased and therefore TL,NO/ TL,CO to be increased. This has been investigated in VC to be. knowledge, the TL,NO/ TL,CO ratio in PE has not yet been reported in humans. Therefore, the aim of this. prone anesthetized sheep by Harris et al. who reported a significant higher TL,NO/ TL,CO ratio after study was to investigate the value of the TL,NO/ TL,CO ratio in the exclusion of PE.. pulmonary artery obstruction compared to baseline [10]. To the best of our knowledge, the in PE has not yet been reported in humans. Therefore, the aim of this study was TL,NO/ TL,CO2.ratio Methods 2.1 Design to investigate the value of the TL,NO/ TL,CO ratio in the exclusion of PE. This study was conducted at Medisch Spectrum Twente in Enschede, the Netherlands, in combination with another research project on the value of volumetric capnography in pulmonary. 2. Methods. embolism. Inclusion criteria were: patients at the emergency department with suspected PE for. 2.1 Design. 23. This study was conducted at Medisch Spectrum Twente in Enschede, the Netherlands, in combination with another research project on the value of volumetric capnography in pulmonary embolism. Inclusion criteria were: patients at the emergency department with suspected PE for which a CTPA-scan was requested due to either elevated Wells-score or D-dimer and age ≥ 18 The TL,NO / TL,CO ratio cannot be used to exclude pulmonary embolism. 23.

(26) years. Exclusion criteria were: hemodynamic instability, pregnancy and oxygen administration. After inclusion, capnography and CO/NO-diffusion measurements were performed within 4 hours after the request for a CTPA was filed and before the results of the CTPA were reported to the pulmonologist. Both the local ethics committee as well as the board of directors of Medisch Spectrum Twente approved the study protocol.. 2.2 Measurements CO/NO-diffusion was measured on the MasterScreenTM PFT Pro system (CareFusion, Amsterdam, the Netherlands) using the single-breath method with a breath-hold time of 10 seconds and an inspired NO fraction of 50 ppm. According to the ATS/ERS guidelines, a measurement was considered repeatable when the results of at least two tests were within 10% of the highest resulting values for TL,CO and TL,NO and the vital capacity (VC) was at least 85% of the highest VC measured before the diffusion test [11]. Predicted values for TL,CO, KCO and alveolar volume were provided by the MasterScreenTM PFT Pro software. Predicted values for TL,NO and KNO were calculated using the prediction equations of van der Lee et al. [12].. 2.3 Statistical Analysis Continuous variables are expressed as median with interquartile range (IQR); categorical variables as counts with corresponding percentages. Baseline differences between the groups with and without PE were for continuous variables compared using the Mann-Whitney U-test. For categorical variables, the Chi-square test or Fisher’s Exact test were used as appropriate. Diagnostic performances of TL,CO, TL,NO and the TL,NO/TL,CO ratio were quantified with the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. All AUCs were tested against the nullhypothesis that the true area is equal to 0.5. Differences were considered significant if the statistic p is smaller than 0.05. Data were analyzed using SPSS version 22 (SPSS Inc. Chicago IL, USA).. 3. Results Subjects were included from the end of July 2014 till the begin of May 2015. During this period, 36 patients were approached for participation in the study. Five of the approached patients refused participation, leading to 31 included subjects. PE was found in 13 patients on CTPA. Diffusion measurements failed in three patients (two no PE, one PE). Characteristics and presenting symptoms of the included patients are provided in table 1. Three patients in both groups had a history of previous PE or deep venous thrombosis (p=1.000). In the group without PE, three patients had known airflow obstruction versus no patients with known airflow obstruction in the PE group (p=0.238). Wells-score, D-dimer levels and the number of abnormal chest X-rays were significantly higher in the PE group compared to the no PE group. No other significant differences in characteristics were found. 24. Chapter 2.

(27) Table 1 – Patient characteristics. Data are presented as median (interquartile range) unless stated otherwise. BMI denotes body mass index, PE denotes pulmonary embolism, DVT denotes deep venous thrombosis. * indicates a statistically significant difference (p < 0.05). No PE (N=16) Median. IQR. Median. IQR. Age (y). 56. (42 - 69). 49. (41 - 67). 0.415. Females (N (%)). 9. (56.3). 6. (50.0). 0.743. Height (cm). 177. (168 - 183). 177. (166 - 184). 0.816. Weight (kg). 83. (72 - 95). 78. (63 - 98). 0.378. BMI (kg/m2). 29.0. (24.2 - 33,7). 25.3. (23.2 – 28.5). 0.137. Active smoker (N (%)). P-value. 6. (37.5). 2. (16,7). 0.401. Wells-score. 2.8. (0.0 – 3.0). 3.0. (3.0 – 4.5). 0.011*. D-dimer (µg/L). 804. (640 - 1758). 2820. (1097 - 6049). 0.001*. 1. (6.3). 9. (75.0). 0.000*. Abnormal CXR (N (%)). 2. PE (N=12). Thoracic pain (N (%)). 13. (81.3). 8. (66.7). 0.418. Dyspnea (N (%)). 11. (68.8). 10. (83.3). 0.662. Results of the measurements are provided in table 2. A boxplot of the distribution of the TL,CO/ TL,NO ratio in the no PE and PE groups is given in figure 1. No statistically significant differences between the PE and no PE groups were found. TL,CO,TL,NO ratio and alveolar volume were all lowered (< 80% of predicted) in both the PE and no PE groups. AUC of the TL,NO/TL,CO ratio was 0.453 (95% confidence interval (CI) 0.230-0.676, p=0.676). The AUCs of all diffusion parameters were also not statistically significant higher than 0.5. Table 2 – Results of the CO/NO diffusion measurements. Data are presented as median (interquartile range) unless stated otherwise. IVC denotes the inspiratory vital capacity, VA denotes the alveolar volume, TL,CO the transfer factor of the lungs for carbon monoxide, KCO the transfer coefficient of the lungs for carbon monoxide, TL,NO the transfer factor of the lungs for nitric oxide and KNO the transfer coefficient of the lungs for nitric oxide. No PE (N=16). PE (N=12). Median. IQR. Median. IQR. P-value. IVC (L). 3.03. (2.33 – 3.73). 2.86. (2.26 – 3.71). 0.834. IVC % predicted. 81.6. (70.0 – 93.0). 66.4. (61.1 – 90.5). 0.330. VA (L). 4.79. (3.96 – 5.19). 4.40. (3.53 – 5.57). 0.516. VA % predicted. 77.1. (65.5 – 87.8). 71.0. (65.0 – 81.4). 0.353. TL,CO (mmol/kPa/min). 7.16. (5.27 – 8.90). 6.62. (5.21 – 7.45). 0.330. TL,CO % predicted. 75.8. (62.9 – 89.6). 68.8. (58.5 – 75.7). 0.120. KCO (mmol/kPa/min/L). 1.47. (1.35 – 1.62). 1.46. (1.20 – 1.80). 0.926. KCO % predicted. 99.9. (85.8 – 111.7). 100.5. (87.7 – 107.3). 0.610. TL,NO (mmol/kPa/min). 29.9. (23.0 – 37.9). 25.8. (20.0 – 30.3). 0.286. TL,NO % predicted. 69.3. (57.0 – 76.1). 60.5. (46.6 – 68.9). 0.078. KNO (mmol/kPa/min/L). 6.10. (5.24 – 7.10). 5.98. (5.33 – 6.81). 0.642. KNO % predicted. 89.5. (76.4 – 95.5). 83.9. (77.0 – 91.1). 0.330. TL,NO / TL,CO. 4.09. (3.83 - 4,40). 4,00. (3,78 - 4,32). 0,959. The TL,NO / TL,CO ratio cannot be used to exclude pulmonary embolism. 25.

(28) Figure 1 – Boxplots of the distribution of the TL,NO/TL,CO ratio in the no PE and PE groups. The value of the TL,NO/ TL,CO ratio found in healthy subjects by van der Lee et al. was 4.36 ±0.6 [9].. 4. Discussion Due to the results of Harris et al., and the physiological theory behind the TL,NO/TL,CO ratio, it was expected that the ratio is increased in PE compared to no PE patients. Our data show lowered TL,CO and TL,NO and normal TL,NO/TL,CO ratios in both groups. The value of TL,CO in PE has been investigated several times. Wimalaratna et al. for instance reported a TL,CO of less than 75% of predicted in PE patients which failed to normalize within three months in most cases [13]. Oppenheimer et al. report decreased TL,CO values in chronic thromboembolic disease [14] but it is hard to compare these values to acute PE. In 2011, Piirilä et al. reported lowered TL,CO in acute PE similar to the values found by Wimalaratna et al. (74% of predicted) which were still lowered after seven months [15]. The TL,CO values we found (69% of predicted) are comparable with the results of both Wimalaratna et al. and Piirilä et al. Besides the difference in TL,CO, Piirilä et al. also investigated other parameters (including Dm and VC). Although they did not find a significant difference in Dm/VC ratio (on which the TL,NO/ TL,CO ratio is dependent) and VC between the PE group and the healthy controls, they did observe significant lower values of Dm between the PE group and the healthy controls in both the acute phase and after seven months. Moreover, they reported a (weak) correlation between Dm and the extent of the pulmonary embolism measured by central embolism mass (r=0.31, p=0.047). Piirilä et al. argue that Dm is influenced more by the reduction in alveolar volume compared to VC. As TL,NO is directly related to Dm, this argument agrees with the finding of van der Lee et al. 26. Chapter 2.

(29) that TL,NO is influenced more by a reduction in alveolar volume than TL,CO [12]. Moreover, from table 2 a trend towards lower TL,CO and TL,NO compared to predicted in the PE group compared. 2. to the no PE group can be seen (though not statistically significant due to a small number of subjects). Concluding, the present findings do not correspond with the data of Harris et al. found in sheep but are consistent with earlier measurements of TL,CO in PE in humans. First of all, a probable cause of the lack in increased TL,NO/ TL,CO ratios might be the relatively small extent of the pulmonary emboli included in the current study, as hemodynamic unstable and oxygen dependent patients were excluded. Moreover, recent research showed that total occluding emboli result in perfusion defects [16], in non-occluding emboli a slight decrease in both Dm and Vc can be expected. Finally, hypocapnic bronchoconstriction might shift ventilation towards well perfused regions [17] which could also diminish the negative effects of PE on the diffusion capacity of the lungs. Detailed inspection of the current data reveals another possible explanation for the lack in increased TL,NO/ TL,CO ratios. The measured alveolar volume is decreased in both groups (77.1% of predicted in the no PE group versus 71.0% of predicted in the PE group). This decreased alveolar expansion is likely to be caused by the thoracic pain of which almost all patients suffered (see table 1). This hypothesis is supported by the reduced inspiratory vital capacity in both groups, indicating an extrathoracic restriction. A reduced alveolar volume greatly influences the measured transfer factors. A reduction in alveolar volume will decrease the surface area and increase the thickness of the alveolar-capillary membrane (and therefore decreases Dm and thus TL,NO). TL,CO is approximately equal dependent on Dm and VC and is therefore less dependent on a decrease in alveolar volume. Therefore, the TL,NO/ TL,CO ratio decreases with a decrease in alveolar volume. [12,18] This might explain the slightly lowered TL,NO/ TL,CO ratios found in our data. In the data of van der Lee et al. an alveolar volume of 70-80% of its value at total lung capacity (TLC) results in a measured TL,NO/ TL,CO ratio of approximately 4.00 [12] which corresponds with the now presented data. The previous reports of Wimalaratna et al. and Piirilä et al. on TL,CO in PE do not report alveolar volumes compared to its predicted value. They do report KCO compared to its predicted value. Piirilä et al. report normal KCO values indicating decreased alveolar volumes which corresponds with our data. Surprisingly, Wimalaratna et al. report lowered KCO values when compared to their predicted value (calculated from mean data). This difference can be caused by changes between 1989 and now in measurement protocol and the reference equations used to calculate predicted values.. 5. Conclusion Our data indicate that the TL,NO/ TL,CO ratio cannot be used in the exclusion of pulmonary embolism. Lowered TL,CO and TL,NO combined with normal KCO and KNO were noted in both the no PE and the PE group. The decrease in transfer factors is likely to be caused by the decreased The TL,NO / TL,CO ratio cannot be used to exclude pulmonary embolism. 27.

(30) alveolar volume (possibly due to thoracic pain) which was also noted in both groups. The present findings do not correspond with the TL,NO/ TL,CO ratio found in sheep but are consistent with earlier measurements of TL,CO in pulmonary embolism in humans.. Acknowledgements The authors would like to thank all who have contributed to this study. A special thanks goes to: M. Mulder, M. Vlutters, G. Snel, R. Bruggink and X. Hoppenbrouwer.. Conflicts of Interests The authors declare to have no conflicts of interests.. 28. Chapter 2.

(31) References [1]. Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, et al. D -Dimer for the Exclusion of Acute Venous Thrombosis and Pulmonary Embolism. Ann Intern Med 2004;140:589–602.. [2]. Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416–20.. [3]. Konstantinides S V, Torbicki A. Management of pulmonary embolism: recent evidence and the new European guidelines. Eur Respir J 2014;44:1385–90. doi:10.1183/09031936.00180414.. [4]. Stein PD, Fowler SE, Goodman LR, Gottschalk A, Hales CA, Hull RD, et al. Multidetector Computed Tomography for Acute Pulmonary Embolism. N Engl J Med 2006;354:2317–27.. [5]. Roughton FJW, Forster RE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl Physiol 1957;11:290–302.. [6]. Guenard H, Varene N, Vaida P. Determination of lung capillary blood volume and membrane diffusing capacity in man by the measurements of NO and CO transfer. Respir Physiol 1987;70:113–20. doi:10.1016/S0034-5687(87)80036-1.. [7]. Hughes JMB, van der Lee I. The TL,NO/TL,CO ratio in pulmonary function test interpretation. Eur Respir J 2013;41:453–61. doi:10.1183/09031936.00082112.. [8]. van der Lee I, Gietema HA, Zanen P, van Klaveren RJ, Prokop M, Lammers J-WJ, et al. Nitric oxide diffusing capacity versus spirometry in the early diagnosis of emphysema in smokers. Respir Med 2009;103:1892–7. doi:10.1016/j.rmed.2009.06.005.. [9]. van der Lee I, Zanen P, Grutters JC, Snijder RJ, van den Bosch JMM. Diffusing capacity for nitric oxide and carbon monoxide in patients with diffuse parenchymal lung disease and pulmonary arterial hypertension. Chest 2006;129:378–83. doi:10.1378/chest.129.2.378.. [10]. Harris RS, Hadian M, Hess DR, Chang Y, Venegas JG. Pulmonary Atery Occlusion Increases the Ratio of Diffusing Capacity for Nitric Oxide to Carbon Monoxide in Prone Sheep. Chest 2004;126:559–65.. [11]. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005;26:720–35. doi:10.1183/09031936.05.00034905.. [12]. van der Lee I, Zanen P, Stigter N, van den Bosch JM, Lammers J-WJ. Diffusing capacity for nitric oxide: reference values and dependence on alveolar volume. Respir Med 2007;101:1579–84. doi:10.1016/j.rmed.2006.12.001.. [13]. Wimalaratna HS, Farrell J, Lee HY. Measurement of diffusing capacity in pulmonary embolism. Respir Med 1989;83:481–5.. [14]. Oppenheimer BW, Berger KI, Hadjiangelis NP, Norman RG, Rapoport DM, Goldring RM. Membrane diffusion in diseases of the pulmonary vasculature. Respir Med 2006;100:1247–53. doi:10.1016/j. rmed.2005.10.015.. [15]. Piirilä P, Laiho M, Mustonen P, Graner M, Piilonen A, Raade M, et al. Reduction in membrane component of diffusing capacity is associated with the extent of acute pulmonary embolism. Clin Physiol Funct Imaging 2011;31:196–202. doi:10.1111/j.1475-097X.2010.01000.x.. The TL,NO / TL,CO ratio cannot be used to exclude pulmonary embolism. 2. 29.

(32) 30. [16]. Ikeda Y, Yoshimura N, Hori Y, Horii Y, Ishikawa H, Yamazaki M, et al. Analysis of decrease in lung perfusion blood volume with occlusive and non-occlusive pulmonary embolisms. Eur J Radiol 2014;83:2260–7. doi:10.1016/j.ejrad.2014.08.015.. [17]. Tsang JYC, Lamm WJE, Swenson ER. Regional CO2 tension quantitatively mediates homeostatic redistribution of ventilation following acute pulmonary thromboembolism in pigs. J Appl Physiol 2009;107:755–62. doi:10.1152/japplphysiol.00245.2009.. [18]. Glénet SN, De Bisschop C, Vargas F, Guénard HJP. Deciphering the nitric oxide to carbon monoxide lung transfer ratio: physiological implications. J Physiol 2007;582:767–75. doi:10.1113/ jphysiol.2007.133405.. Chapter 2.

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(35) Volumetric capnography in the exclusion of pulmonary embolism at the emergency department: a pilot study. T.M. Fabius M.M. Eijsvogel I. van der Lee M. Brusse-Keizer F.H. de Jongh. J Breath Res 2016;10:46016. doi:10.1088/1752-7163/10/4/046016..

(36) Abstract Abstract Rationale. The analysis of the of PCO2 expired airairasasaafunction exhaled volume (volumetric capnogRationale: The analysis thein PCO2 in expired function ofof thethe exhaled volume (volumetric raphy) might result ininaamore specific exclusion tool for pulmonary embolism (PE) in addition capnography) might result more specific exclusion tool for pulmonary embolism (PE) in addition to theWells-score Wells-score and D-dimer. A novel combination of volumetric capnography parameters to the A novel combination of volumetric capnography parameters Abstract and D-dimer. should decreased in could PE and could possibly be used (𝑉𝑉𝑉𝑉𝑉𝑉2 × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠⁄𝑅𝑅𝑅𝑅) should be be decreased in PE and possibly be used to decrease the to decrease Rationale: The analysis of the PCO2 in expired air as a function of the exhaled volume (volumetric Abstract number ofof requested computed tomography pulmonarypulmonary angiograms (CTPA). number requested computed tomography angiograms (CTPA). capnography) might result in a more specific exclusion tool for pulmonary embolism (PE) in addition. the. Rationale: analysis of the Pand expiredAair as acombination function of the exhaled volume (volumetric CO2 in Methods:The Volumetric capnography measurements were performed on consecutive patientsparameters seen on to the Wells-score D-dimer. novel of volumetric capnography. Methods. capnography) might in afor specific exclusion tool for pulmonary embolism intoaddition the emergency which, duebeto suspected increased D-dimer level or Wells- the ⁄more (𝑉𝑉𝑉𝑉𝑉𝑉 ×result 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑅𝑅𝑅𝑅 ) should decreased inPE PE(due andto could possibly be (PE) used decrease 2department. capnography were performed on consecutive toVolumetric the Wells-score and D-dimer. Ameasurements novel combination of volumetric parameters patients score), a CTPA was ordered. number of requested computed tomography pulmonarycapnography angiograms (CTPA).. seen on the. emergency department for which, due to suspected PE (due to increased D-dimer level or (𝑉𝑉𝑉𝑉𝑉𝑉 2 × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 ⁄𝑅𝑅𝑅𝑅) should be decreased in PE and could possibly be used to decrease the Results: A Methods: total of 30Volumetric subjects were included, measurements of which in 13 PE wasperformed seen on CTPA. Median PETpatients CO2 was seen on capnography were on consecutive Wells-score), a CTPA wastomography ordered. number of requested computed pulmonary angiograms (CTPA). 4.36 kPa (IQR 3.92 – 4.88)department in the no PEfor group versus kPa (IQR 3.37 – 4.39) in the PED-dimer group level or Wellsthe emergency which, due4.07 to suspected PE (due to increased Methods: Volumetric capnography measurements performed on consecutive seen on ⁄𝑅𝑅𝑅𝑅 was (p=0.086). Mediana of thewas novel parameter 𝑉𝑉𝑉𝑉𝑉𝑉2 were × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 1.85 Pa.minpatients (IQR 1.21 – 3.00) score), CTPA ordered. Results. the department for which, to0.61 suspected to group increased D-dimer levelaor Wellsin emergency the no PE group versus 1.19 Pa.mindue (IQR – 1.39)PE in(due the PE (p=0.006). Using threshold A total of 30 subjects included, of which in 13inPE seen Median CO2 was Results: A total ofwere 30 subjects were included, of which 13was PE was seenon on CTPA. CTPA. Median PETPET CO2 was score), a CTPA was ordered. for the new parameter of 1.90 Pa.min or higher to exclude PE resulted in a negative predictive value 4.36 kPa4.36 (IQR 4.88) in the nonoPE versus 4.07 kPa 3.37 (IQR– 3.37 – the 4.39) in the PE group kPa3.92 (IQR –3.92 – 4.88) in the PE group group versus 4.07 kPa (IQR 4.39) in PE group of 100% (95% CI: 77%-100%) and would have potentially excluded PE in 47% (95% CI: 26% - 69%) of Results: A total of 30 subjects were included, of which in 13 PE was seen on CTPA. Median PET was CO2 was1.85 1.85 Pa.min (p=0.086). Median of the parameter (p=0.086). Median of novel the novel parameter 𝑉𝑉𝑉𝑉𝑉𝑉2 × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠⁄𝑅𝑅𝑅𝑅 was Pa.min (IQR(IQR 1.21 –1.21 3.00)– 3.00) the no PE group without the need of CTPA. 4.36 – 4.88) inversus theversus no PE group versus 4.07 kPa – 4.39) in the(p=0.006). PE group group Using in 3.92 the PE group 1.19 Pa.min (IQR 0.61 –(IQR 1.39) in the PE a threshold in kPa the(IQR no PE no group 1.19 Pa.min (IQR 0.61 –3.37 1.39) ingroup the PE (p=0.006). Using a ⁄𝑅𝑅𝑅𝑅 (p=0.086). Median of the novel parameter 𝑉𝑉𝑉𝑉𝑉𝑉 ×or𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 1.85 Pa.min 1.21 – 3.00) ⁄exclude Conclusion: study introduces a novel 𝑉𝑉𝑉𝑉𝑉𝑉 × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑅𝑅𝑅𝑅 (IQR which is significantly 2 parameter forThis thepilot new parameter of 1.90 Pa.min higher to exclude PE resulted in a negative predictive 2 was threshold for the new parameter of 1.90 Pa.min or higher to PE resulted in avalue negative inpredictive the no PEof group versus Pa.min (IQR 0.61 – 1.39) in potentially the PE group (p=0.006). threshold decreased in100% PE subjects. studies addressing aspects such asexcluded reproducibility anda(95% normalization (95% CI:Future 77%-100%) and would have inUsing 47% CI: 26% - 69%) value of 1.19 100% (95% CI: 77%-100%) and would havePEpotentially excluded PEofin forafter the treatment new the of 1.90 Pa.min or need higher exclude PE resulted negative predictive value needed to confirm its usability in excluding at in theaof emergency noare group without the oftoCTPA. (95% CI: parameter 26% -PE69%) of the no PE group without thePEneed CTPA. department.. 47%. of 100% (95% CI: 77%-100%) and would have potentially excluded PE in 47% (95% CI: 26% - 69%) of Conclusion: This pilot study introduces a novel parameter 𝑉𝑉𝑉𝑉𝑉𝑉2 × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠⁄𝑅𝑅𝑅𝑅 which is significantly the no PE group without the need of CTPA. Conclusion decreased in PE subjects. Future studies addressing aspects such as reproducibility and normalization. This pilotafter study introduces a novel parameter significantly decreased ⁄𝑅𝑅𝑅𝑅 Conclusion: This pilot study introduces ato novel parameter 𝑉𝑉𝑉𝑉𝑉𝑉2in×excluding 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠PE which isissignificantly treatment are needed confirm its usability at which the emergency department. decreased in PE subjects. Future studies addressing aspects as reproducibility and normalization in PE subjects. Future studies addressing aspectssuch such as reproducibility and normalization after after treatmentare are needed needed toto confirm its usability in excluding PE at the emergency treatment confirm its usability in excluding PE at thedepartment. emergency department.. 32. 32. 34. Chapter 3. 32.

(37) 1. Introduction Pulmonary embolism (PE) is a potentially lethal pathology which is hard to diagnose without expensive imaging techniques. Several tools to exclude PE, such as D-dimer [1] and the. Introduction. 3. Wells-score [2] exist. The combination of these tests can safely rule out PE but cannot be. used to confirm it. Thewhich goldis standard for confirming ary embolism (PE) is a potentially lethal pathology hard to diagnose without. PE is a computed tomography pulmonary. (CTPA).[3] toD-dimer the low of the ve imaging techniques. angiogram Several tools to exclude PE,Due such as [1]specificity and the Wells-score. D-dimer and Wells-score for PE, many. CTPAs are most ofcannot the CPTAs to 75%) the result is negative, and PE is ruled out. . The combination of these tests canneeded. safely ruleIn out PE but be used(up to confirm it. The. the search for an additional, fast, cheap ndard for confirming PE[4] is aTherefore, computed tomography pulmonary angiogram (CTPA).[3] Due toand. easily applied screening method to. exclude PE continues. specificity of the D-dimer and Wells-score for PE, many CTPAs are needed. In most of the. In 1959, end-tidal partial carbon dioxide up to 75%) the result is negative, and PEthe is ruled out.[4] Therefore, the search for an pressure. al, fast, cheap and easily applied screening tool method excludeSeveral PE continues. sible screening fortoPE.[5] studies. (PETCO2) has been suggested as pos-. on PETCO2 in suspected PE patients have been. the end-tidal partial carbon dioxide pressure (PETCO2 ) has been as possible performed since (e.g. [6,7]). Mostsuggested of the studies reported. ng tool for PE.[5] Severalwith studies PETCO2 in suspected PE patients have PE. beenHowever, performed PEoncompared to subjects without. a significant lower PETCO2 in subjects. there are many other causes which may. g. [6,7]). Most of the studies a significantPET lower PETCO2 in subjects with PE compared resultreported in a lowered CO2.[8] To gain more information. cts without PE. However, there are many other causeswas whichintroduced, may result in awhich lowered volumetric capnography allows. from capnography measurements,. analysis of the entire curve of exhaled. 8] To gain more information from capnography measurements, volumetric capnography was. CO2. Using this, parameters such as (functional) dead space (which physiologically should be. ced, which allows analysis of the entire curve of exhaled CO2. Using this, parameters such as. increased in PE) can be quantified. In a meta-analysis of 14 studies Manara et al. concluded. nal) dead space (which physiologically should be increased in PE) can be quantified. In a. that (volumetric) capnography might be used to exclude PE in patients with a pretest prob-. nalysis of 14 studies Manara et al. concluded that (volumetric) capnography might be used to. ability less than 10%.[9] However, almost all studies reviewed by Manara et al. only investigated. PE in patients with a pretest probability less than 10%.[9] However, almost all studies. the end-tidal alveolar dead space fraction, i.e. a quantification of the difference in PETCO2 and. d by Manara et al. only investigated the end-tidal alveolar dead space fraction, i.e. a. arterial PCO2 (PaCO2). Verschuren et al. reported the value of several volumetric capnogram char-. cation of the difference in PETCO2 and arterial PCO2 (PaCO2). Verschuren et al. reported the value. acteristics during PE in spontaneously breathing patients.[10,11] Using more characteristics of. al volumetric capnogram characteristics during PE in spontaneously breathing. the total volumetric capnogram (such as the slope of the alveolar phase) might add substantial. .[10,11] Using more characteristics of the total volumetric capnogram (such as the slope of. value to the screening capabilities of volumetric capnography. Preliminary collected data. olar phase) might add substantial value to the screening capabilities of volumetric. showed differences in body weight thegroups groups with and without PE. aphy. Preliminary collected data showed differences in body weightbetween between the. As body weight is. known to influence several physiologic processes[12], a new, weight independent, d without PE. As body weight is known to influence severalrespiratory respiratory physiologic parameterparameter combining severalseveral volumetric capnography es[12], a new, weight independent, combining volumetric capnography characteristics was introduced as further. outlined in the indiscussion section. parameter consists eristics was introduced as further outlined the discussion section.This This parameter consists. multiplied the of slope breath mount of CO2 exhaled per breath(VCO (VCO22)) multiplied withwith the slope phaseof III phase (slope III)III. of the amount of CO2 exhaled per. (slope III) divided by the respiratory rate. washypothesized hypothesized that this new parameter by the respiratory rate (𝑉𝑉𝑉𝑉𝑉𝑉2 × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠⁄𝑅𝑅𝑅𝑅).. ItItwas that this new parameter. is decreased in subjects suf-. ased in subjects suffering from PE compared to subjectsto with PE. fering from PE compared subjects with PE.. The Volumetric Capnogram. 2. The Volumetric Capnogram. umetric capnogram, the recorded exhaled PCO2 is plotted as a function of the exhaled volume be divided into three phases (I, II and III). Phase I consists of air originating from the. ing airways, phase II of an admixture of air from the conducting airways and the alveoli and. In a volumetric capnogram, the recorded exhaled PCO2 is plotted as a function of the exhaled. solely of air from the alveoli. The slope of phase III is an indication for the (ventilation). volume and can be divided into three phases (I, II and III). Phase I consists of air originating 33 from the conducting airways, phase II of an admixture of air from the conducting airways and. Volumetric capnography in the exclusion of pulmonary embolism at the emergency department. 35.

(38) the alveoli and phase III solely of air from the alveoli. The slope of phase III is an indication for the (ventilation) homogeneity and perfusion of the lungs.[13,14] Using Fowler’s method the amount of physiological airway dead space (VDaw) can be calculated from the volumetric capnogram.[15]. Figure 1 - Example of a volumetric capnogram where the measured PCO2 (indicated by the solid line) is plotted as a function of the exhaled volume. Phase I consists of air originating from the conducting airways. Phase II consists of the transition to alveolar air; Phase III consists of alveolar air). A linear approximation of phase III is indicated by the diagonal dashed line.. 3. Methods 3.1 Design This study was conducted at teaching hospital Medisch Spectrum Twente in Enschede, the Netherlands. Consecutive subjects seen on the emergency department for which a CTPA due to suspected PE was requested were included in the study during times when the researchers were available. Following the 2014 ESC/ERS guidelines on PE, CTPA was only ordered if Wellsscore > 4 or D-dimer ≥ 500 µg/L[3]. Subjects who were hemodynamic unstable, pregnant, or needed oxygen administration were excluded. Both the local ethics committee (METC Twente, approval number: K14-25) and the board of directors of Medisch Spectrum Twente approved the study protocol.. 3.2 Measurements A volumetric capnogram was obtained using a Novametrix Co2smoPlus mainstream capnograph (Co2smo Plus! 8100, Novametrix Medical Systems Inc, now Philips Respironics Inc., Murrysville, Pennsylvania, USA) contains a CO2 sensor combined with a fixed orifice differential pressure 36. Chapter 3.

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